DEVELOPMENT OF RADIOGRAPHIC DAMAGE DURING THE FIRST 5-6 YR OF RHEUMATOID ARTHRITIS. A PROSPECTIVE FOLLOW-UP STUDY OF A SWEDISH COHORT

Transcription

1 British Journal of Rheumatology 1996;35: DEVELOPMENT OF RADIOGRAPHIC DAMAGE DURING THE FIRST 5-6 YR OF RHEUMATOID ARTHRITIS. A PROSPECTIVE FOLLOW-UP STUDY OF A SWEDISH COHORT E. FEX, K. JONSSON,* U. JOHNSONf and K. EBERHARDT Department of Rheumatology, *Department of Diagnostic Radiology and \Blood Bank, Lund University Hospital, S Lund, Sweden SUMMARY The objective of this study was to describe the development of radiographic damage in patients with RA and to search for predictors of radiographic progression over 5 yr. One hundred and thirteen patients, 75 female and 38 male, mean age 53 yr, with definite RA and mean disease duration of 11.4 months, were followed prospectively for 5 yr at an out-patient clinic. Radiographs of the hands and feet were performed annually, and evaluated according to Larsen. The predictive value of demographic, clinical and laboratory variables at study start was evaluated. A stepwise logistic regression model was applied. We found that radiological joint damage occurred early and was significantly progressive during the 5 study years. The rate of progression was most prominent during the first 2 yr. At study start, 53% of the patients had no detectable erosions, but only 11 % remained non-erosive. Twenty-six per cent of the patients with the initial presence of erosions did not progress substantially and needed no aggressive therapy. High joint damage progression during the first year, female gender and high baseline ESR could predict 57% of the patients with high total radiographic progression. Age, disease duration, rheumatoid factor, genetic factors, active joint count and the presence of erosions at study start had no predictive value. KEY WORDS: Rheumatoid arthritis, Radiographic damage, Prognostic factors. RHEUMATOID arthritis (RA) is a universal disease with far-reaching consequences for the individual and society. The aetiology is still unknown and the disease course is very variable and unpredictable. Outcome of the disease may be considered from many different aspects. Radiographic damage reflects the cumulative effect of the disease process, and gives a lasting picture of bone and cartilage destruction. Repeated assessment of the radiographic changes at two or more points in time gives a more dynamic measure of the rate of progression than a single assessment [1]. Erosions appear early and are presumed to be a bad prognostic sign [2-9]. Ideally, therapy should begin before permanent joint damage occurs, but no clinically useful prognostic factors have been defined. Several studies address the putative importance of various prognostic factors, but the results are conflicting [10, 11]. Thus, rheumatoid factor (RF) correlated with a more erosive and aggressive disease in some [8, 12-14], but not in other studies [15, 16]. The same can be said of age at disease onset and gender [6, 8, 17-22]. Much attention has focused on genetic factors and their linkages to RA. Some genes within the DR-region of the major histocompatibility complex (MHC) are associated with susceptibility to RA, but whether they also are predisposing for a more severe disease is still controversial [5, 21-29]. Most investigators agree that the acute-phase reaction, as measured by C-reactive protein (CRP) and ESR, correlates somewhat to radiological progression [5, 7, 30-32]. It is difficult to validate and draw overall conclusions from these Submitted I November 1995; revised version accepted 26 April Correspondence to: E. Fex. studies. Their design and duration, patient selection and outcome measures are not uniform. The purpose of the present study was to describe the development of radiological changes in patients with RA followed prospectively from an early stage of the disease, and to search for predictors of radiographic progression over 5 yr. In addition, we tried to answer the following questions. Is RA always an erosive and progressing disease? Does early joint damage postulate a bad long-term prognosis? PATIENTS AND METHODS The patients were part of a prospective study and had been actively recruited from primary care units in the area during the years The inclusion criterion was definite RA with a duration of <24 months in patients aged ^ 18 yr [33]. All patients were Caucasians. The results of the 2 yr follow-up have been published [6]. One hundred and thirteen patients have now been followed for 5 yr. They were 38 men and 75 women of mean (S.D.) age 53 (12.8) yr and with mean disease duration (S.D.) 11.4 (6.6) months at inclusion in the study. Seventy-one patients were RF positive at study start and during follow-up another eight patients became seropositive. During follow-up, three patients died (two with cancer and one with heart failure) and another two moved. At study start, 109 of the patients were taking non-steroidal anti-inflammatory drugs (NSAIDs), one patient was treated with low-dose oral corticosteroids and three patients were taking chloroquine. During the 5 yr, 71 patients were treated with disease-modifying anti-rheumatic drugs (DMARDs) for 6 months or more. Twenty-five received low doses of oral corticosteroids at some time. The most commonly used British Society for Rheumatology

2 FEX ET AL.: RADIOGRAPHIC PROGRESSION IN RA 1107 DMARDs were chloroquine (46), D-penicillamine (26), sodium aurothiomalate (9) and auranofin (9). Twenty-four patients received more than one drug and 10 patients more than two. Another nine patients tried DMARD medication during the study period, but had to stop due to side-effects. The mean (s.d.) from inclusion in the study to the start of treatment was 11 (11.5) months and from disease onset 20.5 (13) months. During the observation time of 5 yr, 16 patients had to undergo joint replacement. Fourteen patients had hip joint replacements, six of them bilateral, one shoulder joint and one knee joint replacement. At the time of the first joint replacement, the patients had had their disease an average of 47 months (range months). Clinical assessment The patients were examined every third or sixth month at the out-patient team care unit. The time interval depended on disease activity and DMARD medication. Clinical and laboratory data for this study were collected twice a year with a 6 month interval. Assessment of disease activity consisted of patients reported morning stiffness in minutes (average over the last week), grip strength measured with a sphygmomanometer (mean of right and left hand readings). A Swedish version of the Stanford Health Assessment Questionnaire (HAQ) was used for assessing disability [34] and patients' functional class (FC) was classified according to Steinbrocker et al. [35]. On a visual analogue scale (VAS, 100 mm), the patient recorded pain and general health during the preceding week. In order to facilitate the comparison with HAQ scores, the VAS value in millimetres was multiplied by three and then divided by 100, thus giving a range of 0-3. Active joint counts (AJC) were recorded by a rheumatologist. An active joint was denned as swollen and tender and/or painful on motion. The following 50 joints were included: the temporomandibular, the sternoclavicular, acromioclavicular, shoulder, elbow, wrist, metacarpophalangeal, proximal interphalangeal, hip, knee, ankle, midtarsal and metatarsal joints. Joint tenderness was measured by the Ritchie index, which includes 53 joints: the 50 mentioned above, the cervical spine and the talocalcaneal joints [36]. Remission was defined according to the ARA criteria [37]. Table I shows some characteristics of the patients at study start, and after 2, 4 and 5 yr. Laboratory assessment Biochemical assays used in this study were ESR, haemoglobin level (Hb) and RF. Measurement of RF was performed using an IgG fraction for sensitization of sheep red cells [38]. A titre of 1:64 was considered positive, corresponding to 50 in international units [39]. Genomic DNA was extracted from peripheral blood. HLA-DRB and DQB alleles were typed by restriction fragment length polymorphism analysis with sequence-specific primers as previously described [40]. Eighty-nine (84%) of the patients carried the conserved third hypervariable region sequence (HVR3), 37 (35%) of these carried the epitope on both alleles, 73 (70%) patients were DRB1*O4 positive, 27 (26%) of them homozygous for DRB1*O4. Seventeen patients (16%) had no disease-related allele. Radiographic assessment X-rays of hands and feet were taken at study start and annually for 5 yr. Eighty-four patients were available for radiographic examination at 5 yr follow-up. Of the remaining 29, three patients had died, two had moved and 24 were missed at the 5 yr follow-up but had completed the X-ray year 4. A comparison among the 84 patients having a 5 yr X-ray and the 29 incomplete ones showed no significant difference in baseline variables such as age, disease duration, Hb, ESR, AJC, gender, RF, genetic factors, HAQ, FC or initial joint damage. Thus, we concluded that the 84 patients with completed X-ray at follow-up could be considered representative for the whole sample in the analyses of predictive factors. The patients with incomplete X-ray series were included when possible, especially in the descriptive analysis. We used standard film and an anteroposterior projection. The radiographs were evaluated according to Larsen and Dale [41]. Thirty-two joints were assessed: MCP I-V, IP I, PIP II-V, the wrist, EP I and MTP II-V in both hands and feet. Each joint was compared with a standard reference film. The changes were graded from 0 to 5; 0 being normal; 1, joint space narrowing, periarticular osteoporosis or soft tissue TABLE I Some clinical and laboratory characteristics of the 113 patients, at study start, and after 2, 4 and 5 yr. The values are given as median and (interquartile range) Morning stiffness (min) Pain (0-3) General health (0-3) AJC (0-50) Ritchie (0-78) HAQ (0-3) Hb(g/1) ESR (mm/h) ARA functional dass % 1/II/1II (percentage of patients in each class) 0 60 (15-120) 1.2 ( ) 1.5 ( ) 6 (3-12) 8 (4-12) 0.8 (0.4-U) 126( ) 28 (12-48) 12/87/1 *P < 0.01; **P < Comparing variables at study start and after 2 yr. Wilcoxon's test for paired data (0-90) 1.0 ( ) 1.2 ( )* 3 (2-6)" 2 (0-5)" 0.9 ( ) 130 ( ) 22 (10-43) 20/79/1 4 20(0-60) 1.1 ( ) 1.1 ( ) 3(1-5) 2(0-5) 1.0 ( ) 125( ) 19 (10-41) 14/85/1 5 30(0-60) 1.1 ( ) 1.4 ( ) 3(0-7) 2(0-6) 1.0 ( ) 129 ( ) 27 (14-43) 14/85/1

3 1108 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 11 swelling; 2-5, increasing erosions and destruction. A joint damage score (JDS) was calculated by adding all scores, the wrist multiplied by five, with a theoretical span of The scorings were made by one of two assessors, EF and KJ. EF was trained by KJ, an experienced bone and joint radiologist. When independently scoring 105 complete examinations, we found a correlation of 0.94 (Spearman). Wilcoxon's test for paired data showed no significant difference between the two assessors (P = 0.66). All the X-rays of one individual patient were read at the same time, thus comparing the changes from year to year [42]. Clinical and laboratory information was not available at the time of radiological evaluation. The rate of progression was calculated by subtracting the JDS year by year, and total progression of joint damage over the 5 study years by subtracting JDS at follow-up with first JDS at inclusion. Statistics Differences between groups were tested by Wilcoxon's test for related samples and Mann- Whitney's test for independent samples. The x 2 test was used for discrete data. Correlations were calculated according to Spearman. For calculation of prediction, we used a forward stepwise logistic regression model. The validity of the regression models obtained was tested by the goodness of fit and model x 1 test - A condition for this regression model is that the dependent variable is dichotomous. A stepwise logistic regression model selects the variables with the best predictive value. The result is relative to the interrelation and selection of the included independent variables. Total progression of joint damage from study start to follow-up after 5 yr was used as the dependent variable. We chose to compare the third of the patients with the highest total progression with the remaining two-thirds. This subdivision was made in order to explore whether it was possible to identify the patients with the worst prognosis early in the disease course. As independent variables, we used clinical, laboratory, genetic, radiographic and demographic data at study start. All tests were two tailed. Owing to multiple comparisons, the significance level was set at 0.01 for all statistical tests, except for the stepwise logistic model. This test is a single analysis including all factors simultaneously justifying a significance level of RESULTS The first X-ray was performed ~ 10 months after disease onset (mean 9.4; S.D. 6.1). There was a steady progress in JDS, illustrated in Fig. 1. Correlation between joint damage at study start and 5 yr later was weak (r, = 0.18), but 2-3 yr later in the disease course the JDS correlated strongly with 5 yr outcome (r, = 0.82 and r, = 0.94, respectively). The overall rate of radiographic progression assessed by differences in JDS was most rapid the first 2 yr. The rate then decreased significantly in the third to fourth year (P < 0.01), as shown in Fig. 2. The median value Si a CD 60- O m a»- 40-»H Max A Mki r i i Year FIG. 1. Joint damage score (JDS) from study start to 5 yr follow-up. Median, interquartile range, 95th and 5th percentiles, and min-max values. Wilcoxon's test for paired data was used, comparing each year's JDS with the preceding score. All the annual changes were significant at P < of total progression from study start to 5 yr follow-up was 28 with interquartile range The individual rate of progression was very variable. As an example, Fig. 3 shows the variation in rate of progression over 5 yr for 10 patients with total 5 yr progression around the median. Figure 4a-d shows the distribution and frequency (%) of the seven most damaged joints at study start, after 1 and 2 yr, and at 5 yr follow-up. The most affected joint at all points in time was MTP V. After 5 yr, >60% of the patients had erosions of this joint. Erosions in the wrist joint also started early, progressed and increased in prevalence over the years. At study start, 18% of the patients had erosions only in the feet compared to 11 % with only hand erosions. At the 5 yr follow-up, 10% of the patients still had erosions confined to the MTP joints and no radiological damage of the wrist or finger joints, as seen in Fig. 5. At study start, 60 patients had no erosions, but at the S" ID a to 7O ~ o Mix A Mn Annual Progression FIG. 2. Rates of progression (differences in annual JDS) from study start to follow-up. Median, interquartile range, 95th and 5th percentiles, ajid min-max values.

4 FEX ET AL.\ RADIOGRAPHIC PROGRESSION IN RA i 15 - g Years FIG. 3. Annual rate of progression in 10 patients with a 5 yr total progression around the median (range 31-47). time of the 2 yr follow-up, i.e. 2 yr and 8 months after disease onset, only 12 patients remained free of joint damage. At 5 yr follow-up, two of the 12 patients without erosions were lost to follow-up. The remaining 10 still had no erosions (Fig. 5). One of the non-erosive patients received treatment with chloroquine. Three of the non-erosive patients fulfilled the ARA remission criteria at follow-up [35]. The non-erosive patients at 5 yr differed from the others (103 patients) regarding RF (x 2 P < 0.01), DRB1*O4 tf P < 0.001) and HVR3 (X 1 P < 0.01), but not in gender distribution, age, disease duration or baseline ESR and AJC. Patients in the non-erosive group were more seronegative, and less DR4 positive and HVR3 positive. We found no differences in baseline variables when comparing the 60 patients without initial erosions with the 53 patients with erosions at study start, except for disease duration and joint damage score. The non-erosive patients had a significantly shorter disease duration (P < 0.01), the difference in means being only 3 months. There was a great difference in joint damage during the first 2 yr, but the difference seemed to disappear with time. At year five, mean disease duration 5 yr and 10 months, there was no longer any significant difference in JDS between the patients with erosions at study start and those without, as shown in Table II. Fourteen patients (constituting 26%) with erosions at study start showed no or only marginal progression of total JDS over 5 yr, median 3.5 (range -8-8). These 14 patients did not differ from the other patients with initial erosions regarding gender, genetics, RF status, baseline JDS or age, but they had a significantly lower first ESR (P = 0.009) and slower rate of progression during the first year (P = ). There were no significant changes in disability, as measured by HAQ, from study start to follow-up. Most patients did fairly well, but 25% had a HAQ score of 1.4 or more. Functional class remained roughly the same, as shown in Table I. There was no correlation between HAQ and JDS either at study start or at follow-up (r, = 0.11 and r, = 0.006, respectively). Seventy-one of all the 13 patients were treated with DMARDs for more than 6 months during follow-up. At study start, the treated patients had a higher ESR (P< 0.001), lower Hb (P < 0.01), higher AJC (P < 0.01) and longer morning stiffness (P < 0.01) compared to the non-treated patients. They did not differ in disease duration, pain, general health, gender, RF positivity, age, grip strength, HAQ, FC or genetic factors. At study start, there was no difference in JDS between the treated and non-treated, but the difference became evident as early as 1 yr later, as shown in Fig. 6. At follow-up, the only significant difference between the groups, except for JDS, was ESR which still was higher in the treated group (P = 0.005). Sixteen patients developed severe large joint damage resulting in joint replacement [43]. As a group, these did not differ from the remainder regarding age at onset, disease duration at inclusion, gender, RF positivity, AJC or genotype, but they had a lower Hb (P<0.01) and a higher ESR (P < ). JDS showed no difference. After 1 yr, the 16 patients had a higher JDS, higher ESR and lower Hb (P < for all variables). These differences persisted over the 5 yr of observation. At study end, 11 patients in the joint replacement group had a JDS in the upper quartile and the remaining five had a score over the median. At the 5 yr follow-up, 17 patients had a remission. This had occurred spontaneously in seven and with drug treatment in 10 patients. There was no significant difference in JDS over the years between the 17 patients in remission and the remainder at any of the follow-up X-ray examinations. Three remitting patients were free of erosions, compared to eight in the non-remission group. The patients were divided into two groups based on radiographic progression during the first observation year: one-third with a fast rate of progression and the other two-thirds with a moderate or slow rate of progression. As shown in Table III, the patients with a fast rate of progression had a significantly higher baseline ESR. The JDS did not differ at study start, but with time the differences became more prominent and at follow-up the fast progression group had considerably more damage to the joints. Table IV shows that high disease activity, as measured by ESR, Hb and AJC, correlated moderately with joint damage (JDS) on X-ray examinations 1 yr later. In a stepwise logistic regression model, we used total radiographic progression from inclusion to 5 yr examination as dependent variables. The cut point was set to 1/3 (absolute value >44), thus comparing the third with the highest total progression with the remaining two-thirds. The independent variables

5 1110 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 11 consisted of age, RF, gender, genetic factors, disease duration, active joint count, Ritchie index, ESR, Hb, JDS at study start and progression rate, i.e. changes in JDS, during the first year in the study. As seen in Table V, a high rate of progression during the first year, female sex and a high initial ESR were variables of significance to total progression over 5 yr. They correctly predicted 57% of the patients with high total progression and 93% of the patients with low to moderate progression. Genetic factors and RF had no predictive value. DISCUSSION Many studies concerning prognostic factors for radiographic damage have been performed during recent years. The results are difficult to interpret and compare due to varying study design and patient selection. The present longitudinal study includes patients with a definite diagnosis of RA followed from (a) a rather early stage of disease. Although not strictly population based, the study design allowed the inclusion of all age groups, both men and women, and all degrees of disease severity and aimed to include all new cases occurring in the catchment area around Lund. The distribution of gender, RF positivity and epitope positivity in the cohort was that expected [44]. Our RA cohort therefore seemed fairly representative. Only a few early RA studies have extended their observation time to 5 yr [3, 9, 13, 14, 15, 20, 52]. Radiographic assessment of RA is used as a part of the diagnostic procedure, in therapeutic trials, and to follow the course of the disease. Different scoring methods have been developed, those most commonly used today are the Larsen and the Sharp methods [41,45]. We chose the Larsen method because it includes assessment of both hands and feet, and is less time consuming than the Sharp method [46]. The Larsen method was recommended by EULAR 1977 and 1993 [47] for use in clinical trials Score >=3 HScore >=2 I.J FIG. 4. (a and b)

6 FEX ET AL.: RADIOGRAPHIC PROGRESSION IN RA 1111 (c) (d) Score >=3 as Score >=2 Fio. 4. (a) EKstribution and frequencies (%) of JDS in the seven most affected joints at study start. A score of two indicates erosions and a score of three or more increasing joint destruction, (b) The same as (a), but after 1 study year, (c) The same as (a), but after 2 study years, (d) The same as (a), but at study end, after 5 yr. In accordance with most other studies [2-7], joint damage started early and progressed significantly over the years. The median rate of progression was highest during the first 2 yr. However, the rate of progression for the individual patient was not linear, but highly variable (Fig. 3). This is in agreement with Plant et al. [48], who showed a large variation in radiographic progression over 8 yr and implied that first year events are not always significant for outcome later in the disease course. Importantly, we found that 26% of the patients with erosions at study start did not progress substantially over 5 yr. Brook and Corbett [3] have reported an even higher proportion of non-progressive patients, but their follow-up time was only 2 yr. Erosions often started in the feet and a sizeable number of patients (14-18%) developed them only there during the first 2 yr. As the ACR revised criteria of 1987 [49] take no account of erosions of the feet, patients with mild disease and erosions exclusively in MTP joints might be excluded from early RA studies, leading to the selective inclusion of patients with more severe disease. This has been pointed out earner by Paimela [50]. At the 2 yr follow-up, slightly more than 10% of the patients were non-erosive and they remained so throughout the study. Patients who were prone to developing erosions seemed to do so during the first 2-3 yr of disease. This is in accord with previous findings of Brook and Corbett [3]. The rapidly progressive damage of large joints, mainly hips, during the follow-up time in as many as 14% of the patients was an unexpected finding. All these patients needed joint replacement. We have described this feature in detail previously [43]. These patients also had advanced and rapid progressive radiographic changes of small joints in the hands and feet at the 5 yr follow-up. This was in agreement with Scott et al. [2] and indicated generalized aggressiveness of the disease rather than selectivity for large joint destruction. Score >=3 Score >=2

7 1112 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO M E 80 - o 03 bio 5 as Functional capacity was fairly well preserved over the 5 yr. This has been reported more extensively elsewhere [51]. Our findings are in accordance with some other studies of RA patients with recent onset [8, 52]. Furthermore, disability did not correlate significantly with radiographic findings. As many as one-third of the patients were not treated with DMARDs. The treatment decision was based on clinical judgment. As a group, these patients showed very little radiographic progression, justifying the less aggressive treatment. Furthermore, their functional capacity was fairly well preserved. At study start, the HAQ score (median values) was 0.6 and at follow-up 0.8 (data not shown). We therefore feel that it is not correct to recommend aggressive treatment for all RA patients because of potential toxicity with most drugs. The results also emphasize the need for placebo groups in clinical trials. The TABLE II Comparison of joint damage score (JDS) between patients with and without erosions at study start. Median (interquartile range) N JDS 0 JDS 1 JDS 2 JDS 3 JDS 4 JDS 5 Non-erosive 60 4 (2-7.5) 8.5 (4.5-20) 16.5 (7-32) 22(11-46) 27 ( ) 36 (13-56) 2 3 Years Erosions: FIG. 5. Distribution of JDS in hands and feet over 5 yr. Erosive (6-23) 17.5 (13-32) 31 (16-44) 41.5 (16-53) 43.5 ( ) 48 (17-68) P P = P = P = P /»= non erosive erosions of feet II I II erosions of hands erosions of hands + feet group of patients receiving DMARDs during the study period was very heterogeneous. The patients received different DMARDs, treatment was started at different times in the disease course and the duration of medication varied. Further conclusions about the relationship between treatment and radiographic progression can therefore not be drawn. Radiological status at study start had poor predictiveness for cartilage and bone damage 5 yr later. The correlation was 0.18, explaining only 3% of 2 o 8 <D «E a 70 SO DMAflD MoOUARO k Year Fio. 6. Comparison of joint damage score (JDS) between DMARD recipients and non-recipients during follow-up. Median (interquartile range).

8 FEX ET AL.: RADIOGRAPHIC PROGRESSION IN RA 1113 TABLE III Baseline characteristics and annual JDS for patients with slow and fast rate of progression during the first study year. Cut point 1/3 (>9). Median (interquartile range) N Age (yr) Disease duration (months) Active joint count HAQ Hb ESR Female/male (%) RF pos/neg (%) DRB1'04/04 pos (%) All DRB1*O4 pos (%) AU HVR3 pos (%) JDS 0 JDS 1 JDS 2 JDS 3 JDS 4 JDS 5 Slow (44-61) 9(6-15) 6 (3-10) 0.8 ( ) 128 ( ) 22 (10-36) 74/26 61/ (3-11) 9 (5-14) 14 (8-26) 17(11-39) 20(11-47) 22 (12-50) Fast (41-59) 7 (5-10) 8 (4-14) 0.95 ( ) 121 ( ) 42 (29-66)*" 50/50 67/ (3-11) 28 (21-44)"* 40 (31-53)"* 50 (30-65)*" 51 (36-73)*" 63 (47-92)*" Mann-Whitney test for independent samples. *"/>< P = P = P P = P*> P~ /»= i> P P = P P = P = P P = P P" the variance. However, the rate of radiographic progression during the first year was a much better predictor, as shown in Table III. This was also confirmed in the stepwise logistic regression analysis of predictive factors. The rate of progression turned out to be the single most important factor in predicting total progression over 5 yr. Together with female sex and high ESR at study start, 57% of the patients with the highest total progression could be identified. It should be noted that only 84 patients participated in the logistic regression analysis as 29 patients lacked X-ray at 5 yr follow-up. However, there were no significant differences in baseline data between these two groups. The objective of the regression analysis was to identify prognostic markers, from baseline data, in relation to high radiographic progression over the time period. To further analyse the relationship between JDS and measures of disease activity, the time period between recorded disease activity markers and subsequent radiological examination was shortened to 1 yr (Table IV). This, however, did not strengthen the correlations. ESR was the best single variable, but could only predict 17-34% of the variance in JDS. This is in agreement with empirical observations showing TABLE IV Correlation between the annual JDS and some disease activity variables measured 1 yr before JDS JDS 2 JDS 3 JDS 4 JDS 5 ESR 0.42"* 0.58*** 0.41"* 0.49*" 0.47*" Hb -0.27* -0.27* -0.34*** -0.32* -0.30* AJC *" 0.45"* 0.30* *P<0.0l; " />< TABLE V Stepwise logistic regression with total radiographic progression from study start to study end as dependent variable Variable Progression rate in first year Gender ESR Significance level P < Regression coefficient s.e. Significance that some patients develop severe joint destruction without signs of disease activity. It has been pointed out recently that the process which causes inflammation with joint swelling and tenderness is separate from another causing joint destruction [53]. In agreement with other studies, women had a higher degree of radiographic joint damage over the 5 yr [12, 20-22]. In another study, we investigated the association between genetic markers and radiographic changes in more detail, and found only a weak correlation between the presence of the RA-associated epitope on both alleles and radiographic severity [40]. However, in this study, when several possible predictors were assessed simultaneously, the predictive power of genetic factors was too weak to be practically useful. Moreover, both the HVR3 and RF were present in a large proportion of the patients, 84 and 63%, respectively. At study end, 10 patients were non-erosive and of these only two patients were seropositive. Thus, 97% of the RF-positive patients had erosions at follow-up. Kaarela et al. [54] found that 99% of patients with seropositive RA had developed erosive disease after 17 yr. Similarfindingshave been described by Fuchs et al. [55] and Gran et al. [56]. It is, therefore, not unexpected that the prognostic value of RF, concerning disease severity, was limited in the erosive group. However, in the very small group of patients remaining non-erosive, a negative RF test and a non-ra-associated genotype were significantly more common. Positive IgM RF was a stronger predictor of radiographic outcome in the cohort studied by van Zeben et al. [14]. The diversity of the results may be due to the different age and gender distribution. Their group consisted only of women between 20 and 50 yr of age. In conclusion, radiographic joint damage occurred early in the disease course and the progression was most rapid during the first 2 yr. The presence of early erosions was not always a sign of aggressive disease and the individual rate of progression was highly variable. The best prognostic variables for subsequent high joint damage progression were fast rate of progression during the first study year, female sex and high baseline ESR. Only 57% of the patients with high total progression could be identified. Our study indicates that slow to moderate total radiographic progression was easier to predict since this could be achieved correctly in 93% of patients. Our results do not support

9 1114 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 11 the uniform application of early aggressive treatment in all erosive patients. ACKNOWLEDGEMENTS This study was supported by grants from Alfred Osterlunds Stiftelse, Riksforbundet mot Reumatism, Greta och Johan Kocks Stiftelser, Medicinska fakulteten vid Lunds Universitet and Konung Gustaf V:s 80-arsfond. REFERENCES 1. Sharp JT. Radiologic assessment as an outcome measure in rheumatoid arthritis. Arthritis Rheum 1989;32: Scott DL, Coulton BL, Popert AJ. Long term progression of joint damage in rheumatoid arthritis. Ann Rheum Dis 1986;45: Brook A, Corbett M. Radiographic changes in early rheumatoid disease. Ann Rheum Dis 1977;36: Larsen A, Thoen J. Hand radiography of 200 patients repeated after an interval of one year. Scand J Rheumatol 1987; 16: Mottonen TT. Prediction of erosiveness and rate of development of new erosions in early rheumatoid arthritis. Ann Rheum Dis 1988;47: Eberhardt KB, Rydgren LC, Petersson H, Wollheim FA. Early rheumatoid arthritis Onset, course, and prognosis over 2 years. Rheumatol Int 1990;10: van der Heijde DM, van Leeuwen MA, van Riel PL et at. Biannual radiographic assessments of hands and feet in a three-year prospective follow-up of patients with early rheumatoid arthritis. Arthritis Rheum 1992;35: Fleming A, Crown JM, Corbett M. Prognostic value of early features in rheumatoid disease. Br Med J 1976;l: Kaarela K. Prognostic factors and diagnostic criteria in early rheumatoid arthritis. Scand J Rheumatol 1985; 57(suppl.):l van der Heijde MFM, van Riel PLCM, van Rijswijk MH, van der Putte LBA. Influence of prognostic features on the final outcome in rheumatoid arthritis: A review of the literature. Semin Arthritis Rheum 1988;17: Wollheim FA, Eberhardt KB. The search for laboratory measures of outcome in rheumatoid arthritis. Bailliere's Clin Rheumatol 1992;6: Masi AT, Maldonado-Cocco JA, Kaplan SB, Feigenbaum SL, Chandler RW. Prospective study of the early course of rheumatoid arthritis in young adults: Comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating to outcome. Semin Arthritis Rheum 1976; 5: Scott DL, Symmons DPM, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987;1: van Zeben D, Hazes JM, Zwinderman AH, Vandenbroucke JP, Breedveld FC. Factors predicting outcome of rheumatoid arthritis: Result of a follow up study. J Rheumatol 1993;20: Jacoby RK, Jayson MIV, Cosh JA. Onset, early stages and prognosis of rheumatoid arthritis. A clinical study of 100 patients with 11-year follow-up. Br Med J 1973;2: Eberhardt K, Truedsson L, Pettersson H et al. Disease activity and joint damage progression in early rheumatoid arthritis: relation to IgG, IgA, and IgM rheumatoid factor. Ann Rheum Dis 1990;49: Fleming A, Crown JM, Corbett M. Early rheumatoid arthritis. I. Onset. Ann Rheum Dis 1976;35: van der Heijde MFM, van Riel PLCM, van Leeuwen MA, van't Hof MA, van Rijswijk MH, van der Putte LBA. Older versus younger onset rheumatoid arthritis: results at onset and after 2 years of prospective follow-up study of early rheumatoid arthritis. J Rheumatol 1991;18: Deal CL, Meenan RF, Goldenberg DL et al. The clinical features of elderly onset rheumatoid arthritis. A comparison with younger-onset disease of similar duration. Arthritis Rheum 1985;28: Feigenbaum SL, Masi AT, Karplan SB. Prognosis in rheumatoid arthritis. A longitudinal study of newly diagnosed younger adult patients. Am J Med 1979;66: Scott DL, Grindulis KA, Struthers GR, Coulton BL, Popert AJ, Bacon PA. Progression of radiological changes in patients with rheumatoid arthritis. Ann Rheum Dis 1984;43: Carvalho A, Graudal H, Jorgensen B. Evaluation of the progression of rheumatoid arthritis. Ada Radiol Diagn 1980;21: van der Heijde MFM, van Riel PLCM, van Leeuwen MA, van't Hof MA, van Rijswijk MH, van der Putte LBA. Prognostic factors for radiographic damage andphysical disability in early rheumatoid arthritis. A prospective follow-up study of 147 patients. Br J Rheumatol 1992;31: Eberhardt K, Grubb R, Johnson U, Pettersson H. HLA-DR antigens, Gm allotypes and anti-allotypes in early rheumatoid arthritis their relation to disease progression. J Rheumatol 1993;20: Paimela L, Leirisalao-Repo M, Helve T, Koskimies S. The prognostic value of HLA DR4 and B27 in early rheumatoid arthritis. Scand J Rheumatol 1993;22: Silman AJ, Reeback J, Jaraquemada D. HLA-DR4 as a predictor of outcome three years after onset of rheumatoid arthritis. Rheumatol Int 1986;6: Weyand C, Hicok K, Conn D, Goronzy J. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med 1992;117: Gough A, Faint J, Salmon M et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum 1994; 37: van Zeben D, Hazes JM, Zwinderman AH et al. Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Result of a followup study. Arthritis Rheum 1991;34: Amos RC, Constable TJ, Crockson RA, Crockson AP, McConkey B. Rheumatoid arthritis: relation of serum C-reactive protein and erythrocyte sedimentation rate to radiographic changes. Br Med J 1977;l: Dawes PT, Fowler PD, Clarke S et al. Rheumatoid arthritis: treatment which controls the C-reactive protein and erythrocyte sedimentation rate reduces radiological progression. Br J Rheumatol 1986;25: van Leeuwen MA, van Rijswijk MH, van der Heijde DMFM et al. The acute phase response in relation to radiographic progression in early rheumatoid arthritis. Br J Rheumatol 1993;32(suppl. 3): Ropes MW, Bennet GA, Cobb S, Jacox R, Jessar RA. Diagnostic criteria for rheumatoid arthritis. Ann Rheum Dis 1959;18:49-53.

10 FEX ET AL.: RADIOGRAPHIC PROGRESSION IN RA Ekdahl C, Ebcrhardt K, Andersson SI, Svensson B. Assessing disability in patients with rheumatoid arthritis. Use of a Swedish version of the Stanford Health Assessment Questionnaire. Scand J Rheumatol 1988; 17: Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis. J Am Med Assoc 1949;140: Ritchie DM, Boyle JA, Mclnnes JM et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 1968;37: Pinals RS et al. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981;24: Ball J. Scrum factor in rheumatoid arthritis agglutinating sensitized sheep red cells. Lancet 1950;2: Anderson SG, Bentzon MW, Houba V, Krag P. International reference preparation of rheumatoid arthritis serum. Bull WHO 1970;42: Eberhardt K, Fex E, Johnson U, WoUheim FA. HLA-DR and DQ-typing in a Swedish cohort of early rheumatoid arthritis Limited predictive value for outcome after 2 and 5 years. Ann Rheum Dis 1996; 55: Larsen A, Dale K. Standardized radiological evaluation of rheumatoid arthritis in therapeutic trials. In: Dumonde DC, Jasani MK, eds. The recognition of antirheumatic drugs. Lancaster MTP Press, 1978: Fries JF, Bloch DA, Sharp JT et al. Assessment of radiological progression in rheumatoid arthritis. Arthritis Rheum 1986;l:l Eberhardt K, Fex E, Jonsson K, Geborek P. Hip involvement in early rheumatoid arthritis. Ann Rheum Dis 1994^4: Wordsworth BP, Lanchbury JS, Sakkas LI et al. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci USA 1989;86: Sharp JT, Lidsky MD, Collins LC, Moreland J. Methods of scoring the progression of radiological changes in rheumatoid arthritis. Arthritis Rheum 1971;18: Cuchacovich M, Couret M, Peray P, Gatica H, Sany J. Precision of the Larsen and the Sharp methods of assessing radiologic change in patients with rheumatoid arthritis. Arthritis Rheum 1992;35: EULAR Standing Committee for International Clinical Studies Including Therapeutic Trials, ESCISIT. Newsletter number 5. Minutes of the business meeting held in Barcelona, July 6, Plant MJ, Saklatvala J, Borg AA, Jones PW, Dawes PT. Measurement and prediction of radiological progression in early rheumatoid arthritis. J. Rheumatol 1994;21: Amett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31: Paimela L. The radiographic criterion in the 1987 revised criteria for rheumatoid arthritis. Arthritis Rheum 1992;3: Eberhardt K, Fex E. Functional impairment and disability in early RA Development over 5 years. J Rheumatol 1995;22: van Zeben D, Hazes JM, Zwinderman AH, Vandenbroucke JP, Breedveld FC. The severity of rheumatoid arthritis: A 6-year followup study of younger women with symptoms of recent onset. / Rheumatol 1994; 21: Elson CJ, Thomson SJ, Westacott CI, Bhoola KD. Mediators of joint swelling and damage in rheumatoid arthritis and pristane induced arthritis. Autoimmunity 1992;13: Kaarela K, Luukkainen R, Koskimies S. How often is seropositive rheumatoid arthritis an erosive disease? A 17 year follow-up study. J Rheumatol 1993;20: Fuchs HA, Kaye JJ, CaUahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989;16: Gran JT, Husby G, Thorsby E. HLA antigens in palindromic rheumatism, nonerosive rheumatoid arthritis and classical rheumatoid arthritis. J Rheumatol 1984;ll: